White blood cells called T lymphocytes play critical roles in immune defense against viruses, bacteria, fungi, protozoa, and cancer cells. They are also involved in allergies/asthma due to the development of an unwanted or excessive type of immune response to substances in our environment and in autoimmune diseases that result from the inappropriate attack of these cells on the body?s own tissues. The effector functions of T cells are mediated largely by proteins termed cytokines that either be expressed at the cell surface or secreted. Because T cells see foreign substances (antigens) in the form of peptide-major histocompatibility complex (MHC) molecule complexes on cell surfaces, we wish to know how such complexes interact with specific receptors to evoke the effector activities of mature T cells in the body, as well as regulate their growth, inactivation, or death. In particular, we want to understand in molecular detail the protein-protein interactions that turn recognition of antigen by T cells into signals guiding the function of these cells, how variations in these recognition and signaling events leads to desirable versus undesirable forms of immunity, and how we can manipulate these events to augment useful immune responses and inhibit damaging ones. Our studies currently focus on the intracellular events evoked by binding of the T-cell receptor with peptide:MHC molecule ligands and on new biochemical regulatory pathways that help T-cells discriminate between self- and foreign peptide:MHC molecule complexes, as well as show very high sensitivity to antigen on presenting cells of the types studied in LI545. During the past year, we have been able to demonstrate that human T-cells show the same alternative states of T-cell receptor activation in response to closely related ligands as the mouse cells we previously studied. We have also been able to relate the signaling patterns generated in response to various receptor ligands to the potency of stimulation of effector responses of the T-cells, and to show that there are also changes in a hierarchical organization of response thresholds for different gene activation events. We have shown heterogeneity in individual T-cell responses within populations of T-cells expressing the same antigen receptor. Most significantly, we have discovered novel feedback regulatory pathways that control the quality and extent of intracellular signaling by T-cell receptors.